Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms?

Hydrocodone is a semisynthetic opioid with analgesic and antitussive properties qualitatively similar to other opioid agonists. Ibuprofen is a nonsteroidal antiinflammatory agent with analgesic and antipyretic activity and is an effective, primarily peripheral-acting antiinflammatory analgesic. The objective of this clinical trial was to determine the additive analgesic effect of the combination of 15 mg hydrocodone bitartrate with 400 mg ibuprofen, relative to 400 mg ibuprofen alone and placebo, in the treatment of postoperative pain. The single-dose analgesic efficacy of the combination of hydrocodone bitartrate with ibuprofen was compared with ibuprofen alone and placebo in 120 patients with moderate or severe postoperative pain after abdominal surgery. Analgesia was measured during the 6-hour period after dosing based on onset of relief, hourly and summary variables, and duration of effect. A significantly greater proportion of patients treated with the hydrocodone/ibuprofen combination reported onset of relief compared with ibuprofen or placebo; however, the distribution functions for time to onset of relief did not differ among treatments. Hydrocodone with ibuprofen and ibuprofen alone were significantly more effective than placebo for all measures of analgesia. The combination of hydrocodone with ibuprofen was significantly superior to ibuprofen for all hourly analgesic evaluations, weighted sum of pain intensity differences (SPID), total pain relief (TOTPAR), and global rating of study medication. No patients in the hydrocodone with ibuprofen group required analgesic remedication during the 6-hour study period, compared with 25% and 82% in the ibuprofen and placebo groups, respectively. The analgesic superiority of 15 mg hydrocodone bitartrate combined with 400 mg ibuprofen compared with 400 mg ibuprofen alone was demonstrated across many efficacy variables.     

Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) with strong analgesic activity. The analgesic efficacy of ketorolac has been extensively evaluated in the postoperative setting, in both hospital inpatients and outpatients, and in patients with various other acute pain states. After major abdominal, orthopaedic or gynaecological surgery or ambulatory laparoscopic or gynaecological procedures, ketorolac provides relief from mild to severe pain in the majority of patients and has similar analgesic efficacy to that of standard dosages of morphine and pethidine (meperidine) as well as less frequently used opioids and other NSAIDs. The analgesic effect of ketorolac may be slightly delayed but often persists for longer than that of opioids. Combined therapy with ketorolac and an opioid results in a 25 to 50% reduction in opioid requirements, and in some patients this is accompanied by a concomitant decrease in opioid-induced adverse events, more rapid return to normal gastrointestinal function and shorter stay in hospital. In children undergoing myringotomy, hernia repair, tonsillectomy, or other surgery associated with mild to moderate pain, ketorolac provides comparable analgesia to morphine, pethidine or paracetamol (acetaminophen). In the emergency department, ketorolac attenuates moderate to severe pain in patients with renal colic, migraine headache, musculoskeletal pain or sickle cell crisis and is usually as effective as frequently used opioids, such as morphine and pethidine, and other NSAIDs and analgesics. Subcutaneous administration of ketorolac reduces pain in patients with cancer and seems particularly beneficial in pain resulting from bone metastases. The acquisition cost of ketorolac is greater than that of morphine or pethidine; however, in a small number of studies, the higher cost of ketorolac was offset when treatment with ketorolac resulted in a reduced hospital stay compared with alternative opioid therapy. The tolerability profile of ketorolac parallels that of other NSAIDs; most clinically important adverse events affect the gastrointestinal tract and/or renal or haematological function. The incidence of serious or fatal adverse events reported with ketorolac has decreased since revision of dosage guidelines. Results from a large retrospective postmarketing surveillance study in more than 20,000 patients demonstrated that the overall risk of gastrointestinal or operative site bleeding related to parenteral ketorolac therapy was only slightly higher than with opioids. However, the risk increased markedly when high dosages were used for more than 5 days, especially in the elderly. Acute renal failure may occur after treatment with ketorolac but is usually reversible on drug discontinuation. In common with other NSAIDs, ketorolac has also been implicated in allergic or hypersensitivity reactions. In summary, ketorolac is a strong analgesic with a tolerability profile which resembles that of other NSAIDs. When used in accordance with current dosage guidelines, this drug provides a useful alternative, or adjuvant, to opioids in patients with moderate to severe pain.     

Nursing science in German--current status and future prospects

Metastatic bone disease is a frequent cause of morbidity in advanced cancer patients with a subsequent high incidence of skeletal complications (fractures, hypercalcemia, spinal cord compression) and severe pain. The osteolytic process is mainly characterized by an osteoclastic activity of bone resorption and inflammatory activity provoked by various cytokines and prostaglandins. Bisphosphonates represent a new class of drugs with inhibitory activity on bone resorption and on inflammatory processes which revealed themselves to be efficacious in a series of clinical conditions such as tumour-induced hypercalcemia, Paget's disease, osteoporosis and metastatic bone disease. The aim of this review of the literature is to show the analgesic efficacy of the different bisphosphonates in phase III studies carried out on patients with metastatic bone disease. Medline and Cancerlit database from January 1984 to February 1998 have been considered. From the analysis of the published studies it appears that bisphosphonates and, in particular, intravenous Disodium Pamidronate, are not only able to slow down the progression of the disease and to reduce the onset of skeletal complications but also have an analgesic effect and the possibility of improving the quality of life, above all in patients with osteolytic metastases due to breast cancer and multiple myeloma. Bisphosphonates represent a further valid therapy to add to an already consolidated list of therapies such as radio, chemo and endocrine therapy, analgesic drugs, orthopaedic and physiatric in the pain management of patients with bone metastases. These drugs meet with the patients' compliance, are well-tolerated as well as having a good cost/efficacy profile. It still remains to be seen if the newer and more potent bisphosphonates such as Ibandronate and Zoledronate can be administered differently from the intravenous route such as by mouth or by patch which are readily accepted by the patient and, moreover, if these more potent drugs are able to prevent or delay the onset and/or the progression of bone metastases.     

A double-blind, randomized study of naproxen sodium, ibuprofen, and placebo in postoperative dental pain

In a double-blind, parallel, placebo-controlled study, 203 patients with post-operative dental pain following the extraction of one or two bony impacted third molars were randomized to receive a single dose of naproxen sodium 220 mg, ibuprofen 200 mg or placebo. Pain intensity and pain relief were assessed at intervals for 12 hours postdose. Both active drugs demonstrated superior analgesic efficacy over placebo. Naproxen sodium and ibuprofen were comparable both in onset of analgesic action and in pain relief. From 1 to 12 hours postdose, naproxen sodium showed a trend for superior analgesic efficacy compared with ibuprofen; this trend reached statistical significance at the 12-hour time point. Both drugs were well-tolerated and effective analgesics for postoperative dental pain.     

Diabetes mellitus increases the severity of anemia in non-dialyzed patients with renal failure

Therapeutic means for patients with disseminated painful bone metastases in breast cancer are strongly limited. There is a big need of an effective and well tolerated therapy. The aim of this study was to evaluate the efficacy of rhenium-186 HEDP for pain palliation in patients with bone metastases in breast cancer. 17 patients with painful bone metastases taking analgesics received one or more injections of 1295 MB9 rhenium-186 HEDP. In 59% of the patients the therapy resulted in a significant reduction of pain. The duration of pain relief partially hold on up to nine weeks. The main side effects of therapy were a short decrease of platelets and leucocytes and an increase of pain for 1-2 days. As conclusion we found out that therapy with rhenium-186 HEDP can be used complementarily to analgesic therapy and radiation in patients with painful disseminated bone metastases in breast cancer.     

Genetic epidemiology of breast and ovarian cancers

Most civilian and military air traffic control facilities in the United States use rapid rotation shift schedules. These schedules have generally been chosen for social reasons. Safety concerns have been raised because the air traffic controllers (ATCs) often carry an acute sleep debt onto the night-shift where they have little active work to do as they sit in the dark at the nadir of their circadian rhythms. This paper reviews advancing and delaying rapid shiftwork schedules, ATC workload factors as they relate to error rates and safety, and potential countermeasures. Recent studies indicate that ATC performance declines on the night-shift and that ATCs may be falling asleep while on-duty. There is indirect evidence that ATC error rates are highest on the night-shift. There are only limited studies which have evaluated potential countermeasures. The operational significance of the problems associated with ATC shiftwork is not yet clear. Further study is needed.     

Epicondylopathia humeri. The indication for, technic and clinical results of radiotherapy

BACKGROUND: The efficacy of radiotherapy for degenerative-inflammatory disorders is well known, but so far long-term observations and reliable assessment of symptoms according to objective criteria and scores for validation are still missing. PATIENTS AND METHOD: From 1986 to 1991, 104 patients with refractory epicondylopathia humeri were irradiated. 85 patients or 93 elbows (due to double-sided symptoms) were documented in long-term follow-up according to objective criteria. All patients had received intensive therapy. Pain symptoms were quantified in "categories" and "grades" prior to and 6 weeks after radiotherapy and at last follow-up. In addition, the elbow score of Morrey et al. [36] was used for long-term evaluation. The onset of pain symptoms was acute in 41 and chronic in 52 cases. The mean symptom duration prior to radiotherapy was 16 months. Pain was mostly triggered off during professional (46) or sportive activities (23) or spontaneously (11). Fifty-one patients were severely disabled in professional or sportive activities. The involved elbow(s) received 2 radiotherapy series of 6 x 1 Gy (total 12 Gy) with 3 fractions per week; the second radiotherapy series was started 6 weeks after the first series. Mean follow-up was 4 +/- 2 (1 to 8) years. RESULTS: Forty-three patients (50 elbows) achieved "complete pain relief (CR)" in all pain categories: 59% elbows with pain at strain had "complete pain relief", 79% with pain at night, 84% with permanent pain, 80% with pain at rest and 81% with pain at initiation or morning stiffness. Nineteen elbows gained "major pain relief (PR)", i.e. had minor symptoms (maximum grade 1) in all categories. Thus, a total of 69 (74%) elbows responded to radiotherapy. Seventeen patients (19 elbows) were operated because of persistent symptoms or dissatisfaction in long-term follow-up; 7 of those became completely free of symptoms. The Morrey-Score improved by a mean of 18 points from 78 prior to radiotherapy to 96 points at last follow-up. According to the Morrey-Score only 2 patients became worse in long-term follow-up. Two parameters indicated a negative prognosis in multivariate analysis: long symptom duration prior to radiotherapy and immobilisation with plaster (p < 0.05). CONCLUSIONS: Radiotherapy for refractory epicondylopathia humeri is highly effective. Long symptom duration and long-term immobilisation by plaster are negative prognostic factors for treatment outcome. Due to the low side effects and treatment costs, radiotherapy is a good therapeutic option in comparison to conventional treatment methods and surgery in the chronic stage of epicondylopathia humeri.     

Validation of World Health Organization guidelines for pain relief in head and neck cancer. A prospective study

In a prospective study of 167 patients with head and neck cancer, we assessed the causes and mechanisms of pain, as well as the efficacy and side effects of analgesic treatment, along World Health Organization (WHO) guidelines. The majority of patients had pain caused by cancer (83%) and/or treatment (28%), 4% had pain due to debility, and 7% had pain unrelated to cancer. Palliative antineoplastic treatment was performed in 32% of patients. Systemic analgesics were administered on 97% of a total of 8,106 treatment days, and coanalgesics or adjuvant drugs on 100%. The treatment proved to be very successful, as severe pain was experienced only during 5% of the observation period. In the absence of serious side effects, the most frequent symptoms observed were insomnia, dysphagia, anorexia, constipation, and nausea. The use of analgesic and adjuvant drugs along WHO guidelines to treat pain in head and neck cancer is highly effective and relatively safe.     

A short (3-day) course of azithromycin tablets versus a 10-day course of amoxycillin-clavulanic acid (co-amoxiclav) in the treatment of adults with lower respiratory tract infections and effects on long-term outcome

The majority of patients with cancer experience significant pain during their illness. Most cancer pain can be readily managed with oral analgesic therapy. However, cancer pain is often under-treated because of poor communication between physicians and patients and inadequate training of physicians in pain management. A systematic pain-oriented history, pain intensity assessment physical exam, and diagnostic evaluation are needed to delineate the cause of pain. A therapeutic plan can then be tailored to the patient's needs, preferences, and severity of pain. This paper reviews the evaluation and treatment of cancer pain, with guidelines for initiating and monitoring non-opioid and opioid analgesic therapy.     

Structural organization and chromosomal localization of the human hepatocyte growth factor activator gene--phylogenetic and functional relationship with blood coagulation factor XII, urokinase, and tissue-type plasminogen activator

BACKGROUND: This study determined the dose-response relation of intrathecal fentanyl for labor analgesia and described the onset, duration, and quality of analgesia when used as the sole analgesic. METHODS: Eighty-four parturients in active labor who requested analgesia were randomized to one of seven treatment groups. They received 5-45 microg intrathecal fentanyl as part of a combined spinal-epidural technique. Visual analog pain scores were recorded before and at intervals after injection patients requested additional analgesia. The occurrence and severity of pruritus, nausea, and vomiting were also recorded. Maternal blood pressure was recorded before injection and at intervals after injection. Fetal heart rate was recorded before and 30 min after injection. RESULTS: By 5 min after injection, pain scores were significantly different among groups (P < 0.001). Mean duration of analgesia increased to 89 min as the dose increased to 25 microg. Maternal diastolic blood pressure was significantly lower 10 and 30 min after injection. There was no difference among groups in the incidence of pruritus; nausea and vomiting were uncommon. Fetal heart rates did not change after injection. A dose-response curve indicates that the median effective dose of intrathecal fentanyl for labor analgesia is 14 microg (95% confidence interval, 13-15 microg). CONCLUSIONS: Intrathecal fentanyl produces rapid, profound labor analgesia with minimal side effects. These data indicate that there is little benefit to increasing the dose beyond 25 microg when it is used as the sole agent for intrathecal labor analgesia.     

Morphine versus methadone in the pain treatment of advanced-cancer patients followed up at home

PURPOSE: The aim of this study was to evaluate the analgesic and adverse effects and the doses of methadone in comparison to morphine. PATIENTS AND METHODS: A prospective randomized study was performed in a sample of 40 patients with advanced cancer who required strong opioids for their pain management. Patients were treated with sustained-release morphine or methadone in doses titrated against the effect administered two or three times daily according to clinical need. Opioid doses, adjuvant medications, symptoms associated with opioid therapy, pain intensity, and pain mechanisms were recorded. The opioid escalation indices in percentage (OEI%) and milligrams (OEImg) were calculated. The effective analgesic score (EAS) that monitors the analgesic consumption-pain ratio was also calculated at fixed weekly intervals. RESULTS: differences in pain intensity were found. Patients treated with methadone reported values of OEI significantly less than those observed in patients treated with morphine. Seven patients in the methadone group maintained the same initial dosage until death, whereas only one patient in the morphine group did not require opioid dose escalation. A more stable analgesia in time in patients treated with methadone was shown by the low number of gaps in EASs reported. Symptom frequencies and intensities were similar in the two groups. CONCLUSION: Methadone is a drug of indisputable value in the treatment of cancer pain, and an unbalanced focus on the risks of inappropriate use rather than the benefits should not compromise the use of a relevant alternative to morphine in the management of cancer pain.     

Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis

PURPOSE: To assess the efficacy and safety of nonsteroidal antiinflammatory drugs (NSAIDs) in the treatment of cancer pain by meta-analyses of the published randomized control trials (RCTs). PATIENTS AND METHODS: Twenty-five studies met inclusion criteria for analysis. Of these, 13 tested a single-dose effect, nine multiple-dose effects, and three both single- and multiple-dose effects of 16 different NSAIDs in a total of 1,545 patients. Baseline pain intensity (when provided) of moderate or higher was indicated in 81% of patients. RESULTS: Single-dose NSAID studies found greater analgesic efficacy than placebo, with rough equivalence to 5 to 10 mg of intramuscular morphine. Pain scores differed insignificantly for aspirin versus three other NSAIDs. Analgesic responses to low- and high-dose NSAIDs suggested a dose-response relationship, but this was not statistically significant. Recommended and supramaximal single doses of three NSAIDs produced comparable changes in pain scores, which indicates a ceiling analgesic effect. Common side effects included upper gastrointestinal symptoms, dizziness, and drowsiness. The incidence of side effects showed a trend to increase with dose, without a ceiling effect, and to increase with multiple doses. Single or multiple doses of weak opioids (WO) alone or in combination (WO/C) with nonopioid analgesics did not produce greater analgesia than NSAIDs alone. Single doses of WO/C analgesics produced more side effects than NSAIDs alone, although both side effect incidence and patient dropout rates were equal when multiple doses were administered. CONCLUSION: These findings question whether the traditional World Health Organization (WHO) second analgesic step (addition of a weak opioid when pain is inadequately treated by a nonopioid analgesic alone) is warranted. A lack of comparable studies precluded testing the hypothesis that NSAIDs are particularly effective for malignant bone pain.     

Analgesia for trauma and burns

This article has described the physiologic impact of trauma- and burn-related pain as well as the effect of a clinician's choice of analgesic method, using the specific example of regional analgesia for pain caused by chest trauma. It has been observed that trauma exerts a holistic influence upon the organism, marshalling reflexes, multi-system physiologic stress responses, and psychologic responses--some adaptive and others maladaptive. There is reason to consider that timely analgesia can intervene in this dynamic process and interdict the establishment of a debilitated state. A key finding of these studies is that a report of pain relief may not be the best outcome measure since the choice of analgesic method(s) has a significant impact on the secondary effects of pain. Although extrapolated from studies of perioperative pain, findings do suggest that there may be a critical period of time during which the secondary effects of a painful stimulus may be attenuated or reversed. How long this period of reversibility exists has not been determined, so planning for the level and goals of analgesia intervention should occur early on. Analgesia should be viewed not only as a humanitarian gesture, but also a therapeutic maneuver with the goal being the early restoration of function and the mitigation of a chronic debilitated state. There is scattered evidence that regional analgesic techniques using local anesthetics have some advantages over other analgesic modalities, particularly in the trauma patient with pulmonary compromise; however, as with other medical interventions, one should develop a strategic plan of application which includes consideration of potential complications and side effects, in addition to the potential therapeutic effects. The traumatized body, as well as the attending physician, must deal with inflammation, the neurohumoral reaction, musculoskeletal reflex responses, and numerous other reactions designed to stabilize an acutely destabilized systemic entity. Multimodal analgesia, with the balanced use of systemic and regional medications, has given the best short- and long-term results in studies of postthoracotomy pain. The use of a similar combined plan for posttraumatic analgesia seems logical; however, many questions remain as yet unanswered. In particular, what are the optimal combinations of techniques/medications to employ to maximize analgesia and minimize secondary effects of trauma? Can an aggressive multimodal approach intervene effectively in the development of chronic pain states, and if so, for how long? What are the long-term benefits to be derived from making a significant impact on the stress response? Last, but not least, can analgesic interventions be shown to be cost-effective according to current societal pressures to reduce the cost of health care? These and other questions are not easy to answer. Trauma strikes, in a variable fashion, patients of all ages, with all forms of comorbidity, and is treated by a technology that continues to evolve. Previous research related to the effects of analgesic treatments has been hampered by the limitations that arise when isolated groups embark on vast projects with limited numbers of patients available. It is time for investigators at multiple centers to embark on coordinated efforts to address long-term questions related to trauma and the therapeutic efficacy of analgesia.     

Touch relieves stress and pain

The contribution of non-biomedical factors to the experience of pain in the cancer patient has not been well established. Although intensity of pain reports cannot be fully explained by extent of identifiable nociception or neuropathy, behavioral factors have been only modest predictors of cancer pain report. Most studies that have demonstrated associations between pain and behavioral factors were conducted with highly selected groups of patients with all data collected concurrently. Thus the predictive value of the behavioral factors has been indeterminable. In this study, 358 bone marrow transplant patients (196 male, 162 female) completed pretransplant biomedical, physical functioning, psychological and social evaluations. For 25 days following transplantation, patients completed daily visual analogue scale oral pain reports and nurses recorded opioid use. At least once a week oral medicine staff completed a standardized, validated measure of observable oral mucositis as a measure of nociception. Results indicated that psychological and social variables were significant predictors of pain in this sample. Distress, particularly distress specific to the transplant, was the strongest predictor, while self-efficacy and coping style were weaker, but significantly associated with pain report for either men or women. While the psychological and social variables were significant predictors of pain, most of the variance in pain report was explained by biomedical variables rather than psychological or social variables. These results are consistent with those of previous research and indicate that biopsychosocial associations predate the onset of pain, but are at best modest predictors of cancer patients who will report greater or lesser pain. Clinical applications and limits of these data are discussed, particularly in relation to emotional distress, coping style and the differences found in predicting pain in men and women.     

Causes and treatment of bone pain of malignant origin

Pain relief has been one of the oldest and most important duties of the physician. There has been little change with regard to this obligation of all caregivers. One-third of patients with advanced cancer will develop clinically relevant skeletal metastases and chronic pain during the course of their disease. All physicians involved in the treatment of cancer patients should know the basic principles of pain treatment. These are described in the following article with special regard to bone pain of malignant origin. Correct assessment of pain intensity and frequency, as well as of the probable causes of pain, and the administration of adequate analgesic treatment should achieve satisfactory results in the vast majority of patients. Every physician should obtain detailed knowledge of the indications and adequate administration of pain-killing therapy as well as possible adverse effects and their successful treatment. It is important in particular to concentrate on a few nonsteroidal anti-inflammatory drugs (NSAIDs) as well as opiates. Knowledge of adequate doses, maximal recommended daily doses, pharmacological properties, important adverse effects and interactions is essential for success in the daily routine. Only by selecting 2 or 3 drugs from each step in the analgesic ladder (WHO) will the nonspecialised physician obtain sufficient experience for optimal analgesia. Physicians should also not hesitate to contact other specialists (medical oncologists, radiotherapists, neurosurgeons, anaesthesiologists and others) in order to maximise benefit for an individual patient.